The brain is a sophisticated organ. When the brain is injured, the drug is not easy to enter the brain. It is difficult to break through the bottleneck due to a special structure of brain-blood-brain barrier (abbreviated as BBB). It is a natural barrier located between blood vessels and brain, which can selectively block certain substances via the blood into the brain. Except oxygen, carbon dioxide and glucose molecules, the blood-brain barrier prevents almost any substance from entering into the brain tissue. The molecular structure of most drugs and proteins are too large, which is impossible to pass the blood-brain barrier. Although the blood-brain barrier can avoid toxic pathogens entering into the central nervous system, it also obstructs the development of therapeutic drugs for the brain.
According to the previous studies, using a focused ultrasound (FUS) with ultrasound contrast agent (UCA) to radiate in a particular area of the brain can non-invasively induce the area of the blood-brain barrier to open shortly. This allows chemotherapy drugs or antibodies with a wide range of molecular sizes to pass across the blood-brain barrier. Although the focused ultrasonic technique can significantly improve the effectiveness of drug delivery, it cannot be used to know the concentration variation when the drug releases from the blood vessels into the brain tissue. If one can predict or measure out how much drug can be transported to the target area at each time point, it will significantly enhance the potential impact of drug delivery on the ultrasound-induced blood-brain barrier opening in the brain.
In order to predict how much drug will be transported to the brain, it requires to find the permeability of the blood-brain barrier. It is known that dynamic contrast-enhanced MRI (DCE-MRI) through signal intensity changes of DEC-MRI contrast agent can be used to monitor the vascular permeability changes when opening the blood-brain barrier over time. In addition, using the pharmacokinetic model proposed by Tofts and Kermode in 1991 (see Magn.625 Reson. Med. 17 (2) (1991) 357-367) can estimate the permeability of the MRI contrast agent. Park et al. applied the theory to propose a mathematical model to estimate the recovery period of the blood-brain barrier Ktrans(t)=Ktrans0×exp(−t/R) (please refer to Journal of Controlled Release 2012 Aug. 20; 162 (1):134-42). In Park's model, it only considers the permeability changes of the ultrasonic irradiation area (half brain), for estimating the length of time to open and close the blood-brain barrier through the half-life. However, for future applications, if it only assesses the decay rate of the target area, it might be inadequate. After all, the impact of decay rate is affected by the differences between individuals. Thus, if it does not consider the difference as a control, it cannot clearly point out the closing time of the blood-brain barrier.